Graves' disease (GD) is a common autoimmune disorder with genetic predisposition. There is strong evidence that the Chr.5q31-33 region, which contains the immune response cytokine genes [interleukin (IL)-3, IL-4, IL-5, IL-9, and IL-13], is linked to autoimmune thyroid disorders in Chinese and Japanese populations. The aim of the present study is to elucidate whether the single nucleotide polymorphisms (SNP) and the interaction of variants in the 5 genes are associated with the development of GD and Graves' ophthalmopathy (GO).GD patients (no.=751), with 190 of GO patients and healthy control subjects (no.=748) were included in this study. Six SNP [rs40401 (IL-3), rs2070874 (IL-4), rs2069812 (IL-5), rs1859430 (IL-9), rs2069868 (IL-9), and rs20541 (IL-13)] were genotyped by SNPstream Genotyping System.There was a significant increase of C allele of rs40401 in GD [odds ratio (OR)=1.18 [95% confidence interval (CI): 1.02-1.36], pallele=0.028] and GO [OR=1.30 (95%CI: 1.04-1.63), pallele=0.022] patients compared with those in the controls. The C allele of the rs2069812 was also significantly associated with GD [OR=1.22 (95%CI: 1.04-1.44), pallele=0.015] and GO [OR=1.45 (95%CI: 1.13-1.86), pallele=0.003] patients. Haplotype analysis showed a predominant increase of the 2 SNP (rs40401-rs2069812, CC) and all the 6 SNP (CCCCCC) haplotype in GD (OR=1.70, OR=3.70, respectively) and even stronger in GO (OR=2.18, OR=7.01, respectively) patients.The results suggested that the polymorphism of IL-3 (rs40401) and IL-5 (rs2069812) were associated with GD and GO susceptibility in Chinese population. The interaction of 6-locus from the 5 genes might confer higher risk for GD and GO than single risk allele.